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Learning Objectives After completing this course, the reader will be able to: Identify genetic variants of glutathione S-transferase and uridine diphosphoglucuronosyl transferase that have been shown to affect clinical outcomes in patients with cancer and describe the general effects of these variants with respect to standard treatment.Describe potential treatment considerations in patients with cancer who have genetic polymorphisms that affect Phase II metabolism of anticancer drugs. CME This article is available for continuing medical education credit at CME.TheOncologist.com Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed.

Learning Objectives After completing this course, the reader will be able to: Identify genetic polymorphisms within pharmacodynamic candidate genes that are potential predictive markers for treatment outcome with anticancer drugs.Describe treatment selection considerations in patients with cancer who have genetic polymorphisms that could influence pharmacodynamic aspects of anticancer therapy. CME This article is available for continuing medical education credit at CME.TheOncologist.com Response to treatment with anticancer drugs is subject to wide interindividual variability. This variability is expressed not only as differences in severity and type of toxicity, but also as differences in effectiveness. Variability in the constitution of genes involved in the pharmacokinetic and pharmacodynamic pathways of anticancer drugs has been shown to possibly translate into differences in treatment outcome. The overall knowledge in the field of pharmacogenetics has tremendously increased over the last couple of years, and has thereby provided opportunities for patient-tailored anticancer therapy. In previous parts of this series, we described pharmacogenetic variability in anticancer phase I and phase II drug metabolism and drug transport. This fourth part of a four-part series of reviews is focused on pharmacodynamic variability and encompasses genetic variation in drug target genes such as those encoding thymidylate synthase, methylene tetrahydrofolate reductase, and ribonucleotide reductase. Furthermore, genetic variability in other pharmacodynamic candidate genes involved in response to anticancer drugs is discussed, including genes involved in DNA repair such as those encoding excision repair crosscomplementing group 1 and group 2, x-ray crosscomplementing group 1 and group 3, and breast cancer genes 1 and 2. Finally, somatic mutations in KRAS and the gene encoding epidermal growth factor receptor (EGFR) and implications for EGFR-targeted drugs are discussed. Potential implications and opportunities for patient and drug selection for genotype-driven anticancer therapy are outlined.

Learning Objectives After completing this course, the reader will be able to: List currently identified candidate genes involved in phase I metabolism that are potential pharmacogenetic markers in anticancer therapy.Describe the general effect on standard treatment of allelic variants of the candidate genes and the implications for individualized treatment. This article is available for continuing medical education credit at CME.TheOncologist.com Equivalent drug doses in anticancer chemotherapy may lead to wide interpatient variability in drug response reflected by differences in treatment response or in severity of adverse drug reactions. Differences in the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of a drug contribute to variation in treatment outcome among patients. An important factor responsible for this variability is genetic polymorphism in genes that are involved in PK/PD processes, including drug transporters, phase I and II metabolizing enzymes, and drug targets, and other genes that interfere with drug response. In order to achieve personalized pharmacotherapy, drug dosing and treatment selection based on genotype might help to increase treatment efficacy while reducing unnecessary toxicity. We present a series of four reviews about pharmacogenetic variability in anticancer drug treatment. This is the second review in the series and is focused on genetic variability in genes encoding drug transporters (ABCB1 and ABCG2) and phase I drug-metabolizing enzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DPYD, CDA and BLMH) and their associations with anticancer drug treatment outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are presented.